When a ligand is bound to a chemokine receptor, migration of leukocytes is induced. Human CC chemokine receptor 4 (hereinafter referred to as CCR4) which is mainly expressed on a Th2-type CD4-positive helper T cell in a normal tissue is one type of a chemokine receptor family [Int. Immunol. 11, 81 (1999)]. CCR4 binds specifically to MARC (thymus and activation-regulated chemokine) or MDC (macrophage-derived chemokine). The Th2-type CD4-positive helper T cell which controls humoral immunity is considered to play an important role in allergic diseases or autoimmune diseases.
In T cell-type leukemia/lymphoma cells described above, various chemokine receptors are expressed, and there is a relation between subtypes of T cell leukemia/lymphoma and types of receptors expressed in cells. It was reported that CCR4 is expressed at high frequency in leukemia/lymphoma cells [Blood, 96, 685 (2000)]. Since CCR4 is expressed at high frequency in ALK-positive anaplastic large-cell lymphoma and mycosis fungoides, a possibility of CCR4 being a tumor marker having quite a high selectivity in specific carcinomas was suggested [Blood, 96, 685 (2000), Mod. Pathol., 15, 838 (2002), J. Invest. Dermatol., 119, 1405 (2002)]. It was reported that CCR4 is expressed at quite a high frequency also in adult T-cell leukemia (hereinafter referred to as ATL) caused by infection with human T-cell leukemiavirus type I) [Blood, 99, 1505 (2002)]. Regarding the expression of CCR4 in ATL, the expression of CCR4 significantly correlates with bad prognosis [Clin Cancer Res., 9, 3625 (2003)]. Further, CCR4 is selectively expressed in cells of cutaneous Tcell lymphoma (hereinafter referred to CTL) [J. Invest. Dermatol., 119, 1405 (2002)].
Method for treating leukemia/lymphoma is mainly chemotherapy using a combination of plural low-molecular anticancer agents. However, chemotherapy that provides satisfactory therapeutic effects has been so far unknown [Gan to Kagaku Ryoho, 26, Supplement 1, 165-172 (1999)].
Among the CCR4-positive leukemia/lymphoma described above, prognosis of ATL is poor in particular. Concerning patients who suffer from acute or lymphatic leukemia occupying more than 70% of total ATL and have experienced common CHOP therapy (therapy using cyclophosphamide, vincristine, doxorubicin and prednisone in combination), 4-year survival rate is approximately 5% [British J. Haematol., 79, 428-437 (1991)].
In usual chemotherapy, it is sometimes difficult to induce remission because of advent of drug-resistant tumor cells or the like. However, excellent therapeutic results are sometimes obtained by combination of chemotherapy and an antibody. Anti-HER2/neu humanized antibody rhuMAb HER2 (Herceptin/trastuzumab, Roche) exhibited an outstanding effect against breast cancer in combination therapy with a taxane anticancer agent [Clinical Therapeutics, 21, 309 (1999)]. Anti-CD20 human chimeric antibody IDEC-C2B8 (Rituxan/rituximab, IDEC) exhibited an outstanding effect against B cell lymphoma by combination therapy with multiple drug therapy [J. Clin. Oncol., 17, 268 (1999)].
Combination therapy using an antibody and a cytokine is also expected as new immunotherapy against tumors. A cytokine is a general term for various humoral factors that control intracellular interaction in an immune reaction. An antibody-dependent cell-mediated cytotoxic activity (hereinafter referred to as ADCC), one of cytotoxic activities, is induced by binding an antibody to an effector cell such as a mononuclear cell, a macrophage or an NK cell [J. Immunol., 138, 1992 (1987)]. For the purpose of activating an effector cell, combination therapy using a combination of an antibody and a cytokine has been attempted. With respect to B cell leukemia/lymphoma, a clinical test administrating IDEC-C2B8 and interleukin (IL)-2 [British J. Haematol, 117, 828-834 (2002)] or IDEC-C2B8 and granulocyte-colony stimulating factor [Leukemia, 17, 1658-1664 (2003)] in combination has been conducted. However, an outstanding therapeutic effect has not been observed in comparison with use of the antibody alone.
Anti-CCR4 antibody KM 2760 has been known as a therapeutic agent against the CCR4-positive leukemia/lymphoma that selectively reduces tumor cells via ADCC (WO 03/18635). Combined use of an anti-CCR4 antibody and a chemotherapeutic agent or a cytokine has been unknown so far.
In treatment of cancers, especially, leukemia and lymphoma, a therapeutic method that brings forth satisfactory effects has been unknown so far.